Nov. 8-21, 2002
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Headlines @ U.Va.
University’s highest honor is given to Childress

Marva Barnett wins Zintl Award

Computer classes buck trend
Cures to diseases lie in cells and genes
Tackling cells’ mysteries
Medical Center, School of Medicine lay out play for the next decade
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Anthropologist Maurice Godelier to give lectures
Artists show “Wizdumb”
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Cures to diseases lie in cells and genes

Research on stem cells, medicinal chemistry and genetics offers great hope for those who suffer from a broad range of diseases—from diabetes and stroke, to leukemia and Alzheimer’s. Scientists at U.Va. are at the forefront of this work.

Stories by Charlie Feigenoff

Dr. Adam GoldfarbGOLDFARB: WHEN HEALING IS IN THE BLOOD CELLS

When they were first introduced over three decades ago, bone marrow transplants marked a dramatic advance in the treatment of leukemia and other cancers of the circulatory system. It is a truly audacious strategy. The blood-producing cells in the marrow of a cancer patient are completely destroyed by chemotherapy and radiation and then are replaced with bone marrow cells from other donors or from specially treated cells from the patients themselves.

The long-term prospects for the majority of patients who undergo bone marrow transplantation are good, but until their bone marrow is fully regenerated they must be monitored carefully. Because their white blood cell count is initially so low, they are extremely susceptible to infection, a danger that is intensified because their immune system in many cases is deliberately suppressed to prevent them from rejecting the donor marrow.

Researchers have discovered a growth factor that speeds recovery of white blood cells, but the problem of speeding platelet recovery has resisted satisfactory resolution. As Dr. Adam Goldfarb notes, a growth factor to stimulate platelet production has been identified, but it only works in instances where the bone marrow has not been completely destroyed. As a result, most cancer patients must undergo a series of platelet transfusions, a therapy which only provides temporary protection.

Platelets are created by bone marrow cells called megakaryocytes. Rather than increase the rate at which each megakaryocyte generates platelets, Goldfarb, an associate professor of pathology, is concentrating on increasing the number of them. He is doing this by taking a step back into their developmental history to learn more about their progenitor cell, the BFU-E/Meg. This adult stem cell can give rise to red blood cells or megakaryocytes. “We are trying to determine the essential regulatory factors that lead this cell to the megakaryocyte pathway,” Goldfarb says. “This will help us develop a target for drug development.”

Heidi ScrableSCRABLE: A MATTER OF TIMING

Ten years ago when she was a postdoctoral fellow, associate professor of neuroscience Heidi Scrable found herself drawn to one of the fundamental puzzles of cancer research: why a defect in the p53 gene is responsible for so many different kinds of cancer.

The p53 gene produces a protein that helps give cells with damaged DNA time to repair themselves before they divide. People who inherit a faulty version of the p53 gene have an elevated risk of developing cancer because these damaged cells begin to accumulate.

Scrable and her colleagues believed that timing was a key variable. They hypothesized that when the mutant version of p53 is activated while new bone cells are being produced, the result is bone cancer. If it is turned on when breast tissue is being replenished, the result is breast cancer.

To test her theory, Scrable needed a way to turn genes on and off at specific times—and in 1990, there was simply no way to accomplish this. But just last year, she and her colleagues perfected a system that investigators can use to regulate when and for how long virtually any gene is expressed.

Scrable has turned to the simple, well-known mechanism that bacteria use to metabolize lactose, a sugar that is found in milk and other sources. Bacteria have evolved an energy-efficient strategy to create lactose-digesting enzymes only when they are needed.

Under normal conditions, a protein repressor binds to a segment of DNA and turns off the genes that encode enzymes to digest lactose. When lactose appears in the environment, it renders this protein repressor ineffective and the genes turn on. Scrable's challenge was to translate this genetic switch into one that would work in a laboratory mouse. If she succeeded, she would be able to control the timing of gene expression simply by feeding mice lactose-like sugars.

It was an elegant idea but one that proved difficult to realize. The DNAs of bacteria and mammals use the same four chemical letters to spell out the steps needed to produce a protein, but the way they use these letters differs substantially.

Scrable found that literally translating the DNA sequence for the lactose repressor protein from bacteria to mouse did not work. Mammals are exponentially more complex than bacteria and their genetic systems are much more complicated. “In doing the re-encoding, we inadvertently introduced sequences that had an adverse effect on function,” she observes.

After eight years of trouble-shooting, Scrable created a proof of concept: a transgenic mouse that can change its pigmentation when this lactose-activated switch is turned on. Under normal circumstances, it appears albino. Given lactose in its drinking water, the mouse turns brown. Feed it pure water, and it turns white again.

Scrable's system provides researchers with a tight, reversible way to control gene expression in mammals that can be applied to a variety of experimental situations and help us understand the temporal dimensions of genetic diseases. “Among other uses, this system gives us the ability to determine if timing of gene expression affects the kinds of tumors that appear in people with the mutant version of p53,” she says. “We can also find out if these effects can be suppressed or even reversed if the gene is turned off at the right time.”

Roy OgleOGLE: TEST DRIVING STEM CELLS

Ahundred years ago, the automobile was a mechanical marvel, but it didn't really gain acceptance until there was a support infrastructure in place that included roads, bridges and gas stations. The same thing could be said for stem cells today. Inducing adult stem cells to transform themselves into specific types of tissue is a remarkable scientific breakthrough, but it is not enough in itself to yield new therapies. That's why work by researchers like Roy Ogle is so important. Ogle is creating the infrastructure needed to harness stem cells to heal bone fractures and regenerate nerves.

Ogle taps all the techniques of tissue engineering. For instance, in an effort to regenerate sciatic nerves, he is trying out a variety of adult stem cells. These include those extracted from fat tissue as well as stem cells he and M.D./Ph.D. student Sunil Tholpady have identified in the lining of the brain and spinal cord. In addition, he is exploring the different kinds of materials that can be used to create a matrix to hold and organize these cells. Ogle is also experimenting with combinations of growth factors and other substances needed to induce adult stem cells to follow a desired developmental path.

“Stem cell research has led to the most exciting advances in biomedical discovery that I have witnessed. I can't think of a disease or a disorder that doesn't lend itself to stem cell intervention.”

Ogle and his colleagues have found that each line of adult stem cells has an inherent phenotype. In effect, it is prone to be converted to one particular cell type rather than another. For example, adult stem cells derived from fat can be converted to nerve cells in just 24 hours, while it takes two weeks to convert them into bone and cartilage and even longer to induce them to become muscle cells, he found.

This is a limitation in comparison with embryonic stem cells, which are more readily plastic and easily converted to a wide range of cell types. On the other hand, the limitations of adult stem cells increase their potential utility in specific cases. If you are interested in producing high yields of nerve cells, you are much better starting from a fat stem cell than an embryonic one.

MIRMIRA: HELP WANTED: A NEW CELL TO PRODUCE INSULIN

Dr. Raghavendra MirmiraIf you wanted to mix metaphors, you could say that the body's insulin-producing mechanism is our Achilles heel. Insulin is the hormone that enables glucose circulating in our blood to enter cells, where it is translated into energy. In other words, it is absolutely essential for life. Furthermore, when glucose builds up in the blood, it can lead to stroke, heart disease, blindness, and nerve damage.

Unfortunately, there is only one type of cell in the body capable of producing insulin: the beta cell. The problem with beta cells is that there are not very many of them. Thinly spread across the pancreas in tiny islets, they account for no more than 2 percent of all cells in that organ and a minute fraction of all cells in the body. It is the small number of beta cells that makes us vulnerable. It is all too easy for all of them to be destroyed, as in Type I diabetes, or to be damaged, as in Type II.

For Dr. Raghavendra Mirmira, a promising long-term strategy for treating diabetes is not to restore a system that is inherently fragile, but to find a new way of producing insulin within the body. In other words, he is looking to find a more robust and numerous replacement for beta cells.

Mirmira and his colleagues are pursuing this quest on a number of levels. “Broadly speaking, I'm interested in identifying substances that are found only in beta cells and not in others,” he notes. “We then try to determine if these substances regulate the genes responsible for insulin production and to find out if these substances can be used to produce insulin in a different cell type.”

Currently, Mirmira is concentrating on two transcription factors—Pdx1 and Nkx6.1—that play an important role in beta cell insulin production on the genetic level. Interestingly enough, these transcription factors bind to different genes in other cells. Mirmira is concentrating on trying to find out what makes them behave as they do in beta cells.

Here his work dovetails with the pioneering investigations of chromatin being carried on by microbiologist David Allis and other researchers at U.Va. Chromatin is the DNA-protein complex that gives genetic material its basic structure. In Mirmira's view, it may well be the structure of the chromatin that differentiates the beta cell from other cells in the pancreas. If he can find a cell that retains the capacity to adjust its chromatin structure to match that of the beta cell, he might be able to induce it to produce insulin.

KATZ: WHEN FAT CAN BE BENEFICIAL

Dr. Adam KatzIn a country in which 34 percent of the population is overweight and 27 percent is obese, fat has a deservedly bad reputation. Research under way by Dr. Adam Katz and his colleagues demonstrates that fat may have some saving graces. Having fat, though not necessarily being fat, might one day save your life.

Katz has found a variety of progenitor cells in the stromal cells associated with fat tissue. Though more differentiated and less plastic than stem cells found in embryos, these adult stem cells still retain the capacity to transform themselves into other kinds of tissues. Katz's goal is to identify molecular and cellular-level differences among these cells, to assess the limits of their plasticity, and then tease out the best methods to convert them to desirable cell types. For instance, heart muscle derived from adult stem cells could be used to treat patients after a heart attack, while bone cells could be used to heal complex fractures or to treat osteoporosis.

With a gift of $300,000 from former dermatology department chair Dr. Peyton Weary and his family, Katz is focusing on the use of adult stem cells found in fat to produce and repair skeletal muscle. Other projects in his lab involve efforts to regenerate or repair heart muscle, the central nervous system, and bone cells. He is collaborating with Drs. Roy Ogle, Kevin Lee, and Brent French on these efforts.
The adult stem cells that Katz studies have been removed from patients undergoing liposuction, a cosmetic procedure typically used to trim waistlines, not save lives.

Photos by Tom Cogill

Reprinted from the Fall 2002 issue of Explorations


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